“Outcomes of COVID-19 infection in patients with hematological malignancies- A multicenter analysis from Pakistan”

Purpose COVID-19 infection resulting from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) began to spread across the globe in early 2020. Patients with hematologic malignancies are supposed to have an increased risk of mortality from coronavirus disease of 2019 (COVID-19) infection. From Pakistan, we report the analysis of the outcome and interaction between patient demographics and tumor subtype and COVID-19 infection and hematological malignancy. Patients and methods This multicenter, retrospective study included adult patients with a history of histologically proven hematological malignancies who were tested positive for COVID-19 via PCR presented at the oncology department of 5 tertiary care hospitals in Pakistan from February to August 2020. A patient with any known hematological malignancy who was positive for COVID-19 on RT-PCR, was included in the study. Chi-square test and Cox-regression hazard regression model was applied considering p ≤ 0.05 significant. Results A total of 107 patients with hematological malignancies were diagnosed with COVID-19, out of which 82 (76.64%) were alive, and 25 (23.36%) were dead. The significant hematological malignancy was B-cell Lymphoma in dead 4 (16.00%) and alive group 21 (25.61%), respectively. The majority of the patients in both the dead and alive group were on active treatment for hematological malignancy while they came positive for COVID-19 [21 (84.00%) & 48 (58.54%) p 0.020]. All patients in the dead group were admitted to the hospital 25 (100.00%), and among these, 14 (56.00%) were admitted in ICU with a median 11 (6–16.5) number of days. Among those who had contact exposure, the hazard of survival or death in patients with hematological malignancies and COVID-19 positive was 2.18 (CI: 1.90–4.44) times and 3.10 (CI: 2.73–4.60) times in patients with travel history compared to no exposure history (p 0.001). Conclusion Taken together, this data supports the emerging consensus that patients with hematologic malignancies experience significant morbidity and mortality resulting from COVID-19 infection.


Patients and Methods
This is a multicenter, retrospective study which included adult patients with a history of hematological malignancy who were tested positive for COVID-19 presenting at the oncology department of 5 tertiary care hospitals in Pakistan from February 2020 to August 2020. The primary objective was to determine overall clinical outcome, the patient characteristics, clinical presentations, treatments administered, and mortality rate stratified by age, type of malignancy and oncological treatment status for COVID-19 in patients with hematological malignancy.

Results
107 patients with hematological malignancy and COVID -19 positive presented to the hospital during study period. The median age was 35 years. The most represented malignancies were acute leukemia (28.9%), non-Hodgkin's lymphomas (28.9%) with predominantly B cell lymphomas and Hodgkin's lymphoma. Most frequently symptoms were respiratory (41%), fever (32.7%) and diarrhea (4.6%). Around 45.8% patients were admitted to the hospital for acute care while 54.2% had mild disease and were advised home isolation. Overall mortality of the entire cohort was 28%. Of which 51% were admitted in hospital. When stratified for age, increased mortality was reported with age greater than 50 years (10.2%) and those with acute leukemia

INTRODUCTION
The SARS-Cov-2 or COVID-19 also known as novel coronavirus has become a global threat and healthcare concern. Since its outbreak in China at the end of 2019, the pandemic has affected more than a 100 million people worldwide. 1  were not included in this analysis.

Outcomes
The primary objective of the study is to determine overall clinical outcomes of COVID-19 infection in patients with hematological malignancy. Secondary objectives of the study are to determine the patient characteristics, clinical presentations, treatments administered, and mortality rate stratified by age, type of hematological malignancy and oncological treatment status.

Statistical Analysis
The data was entered and analyzed by using SPSS version 23. Calculated medians for all continuous variables and frequencies with percentages for categorical variables. Chi-square test was performed to check the association between the age and mortality.

Presenting symptoms and treatment of COVID-19
As shown in Table 1 80% of these patients fulfilled the criteria of cytokine release syndrome. Lymphopenia was seen in 40% of these patients. The most common COVID19-specific therapies in our dataset were symptomatic treatment with steroids (60%) and anticoagulation (35%). Tocilizumab was used in 6.5%, remdesivir in 2.8% and hydroxychloroquine 3.7% of patients. Of the 49 hospitalized patients, 9% and 15% of the patients needed noninvasive and invasive ventilation respectively.

Outcomes of COVID-19 infection
Overall mortality of the study cohort was 28%. Of the 107 patients, 49 patients (45%) required admission to the hospital. The mortality rate in the admitted patients was 51%. 17 patients were transferred to intensive care unit and the mortality rate amongst these patients was 86%. 46.9% recovered from their illness and were discharged home. Average length of hospital stay was 12 days (1-38 days). When stratified for age, the mortality was 7.4%, 5.6% and 10.2% in the age groups 10-30 years, 31-50 years, and 51-70 years respectively. In our cohort the highest mortality was seen in patients with acute leukemia (12.1%) followed by Non-Hodgkin's lymphoma (5.6%), chronic leukemia (3.7%) and multiple myeloma (3.7%). In addition, a mortality rate of 19.6% was seen in those who were on active oncological treatment. (Table 2) Mortality rate in patients receiving intravenous chemotherapy alone was about 14% and 4.6% receiving chemoimmunotherapy. Subsequent PCR data in the infected patients was available for only 17 patients. In those, the average time to a negative PCR result was 19 days (6-40 days).  [16][17] In our study, the overall mortality mirrors the data the of these studies with an overall mortality of 23% and increasing to approximately 51% in the hospitalized patients and 86% in ICU patients. 50% of deaths were seen in patients younger than 50 years. This is most likely due to the fact that approximately 70% of our patients were in that age group. Therefore, this is likely over represented. It was interesting to note the relatively low numbers of patients of older age admitted to the hospital in our cohort. It could be hypothesized that treatment was deferred for the older patients with multiple co-morbidities in the initial months of the pandemic if they had a relatively stable clinical course. However, it would be interesting to study the outcomes of patients who had their treatment deferred.
Several other findings from our cohort are noteworthy. We analyzed the demographics of COVID-19 patients with hematological malignancy and explored the effect of cytotoxic chemotherapy and various chemo immunotherapy and targeted treatments on the trajectory of COVID-19. The incidence of COVID-19 was found to be more frequent in acute leukemias (29%) followed by non-Hodgkin's lymphoma (27%) and Hodgkin's lymphoma (18%) 18 .
Furthermore, an increase in mortality has been reported in myeloid malignancies (MDS/AML/MPN) than lymphoid neoplasms (NHL/CLL/ALL/MM/HL) (43% vs. 35%), [19][20] which is similar to that seen in our study population. Majority of our study patients were on active treatment and reported a mortality rate of 19.6% in contrast to 10% among patients on surveillance. Interestingly a higher mortality rate (14%) was seen in patients receiving chemotherapy alone compared to a 4.6% receiving chemoimmunotherapy.
The most common COVID-19-specific therapies in our dataset were symptomatic treatment with steroids and anticoagulation, tocilizumab (6.5%), remdesivir (2.8%), hydroxychloroquine (3.7%). The use of tocilizumab and remdesivir in our cohort were low when compared to other studies. 10 One reason is that our data collection started in the early days of the pandemic when these drugs were not used regularly. Additionally, the availability of the drugs was sparse until the mid of 2020. Remdisivir was given emergency use authorization in May 2020 and gained full FDA approval in October 2020. It only then has this drug become widely available for use. Our study has some limitations. Our analyses are based on patients with hematological malignancy who sought help from centers where they were receiving their treatment. Therefore, this cohort did not capture the outcomes of patients who presented for management at a different hospital. This is particularly true for patients who live in another cities or towns and most likely obtained treatment closer to home. Also, we likely missed patients on long term follow-up who approached their local GP or hospital. We, too, were unable to capture those patients who were asymptomatic and found to have COVID-19 positive on screening. In addition, patients who are on hospice care were not reported or included in this study. Therefore, it is not possible to accurately quantify the burden of infection in patients with hematological malignancy.
Nonetheless, this dataset provides the glimpse of outcomes of patients who presented to a tertiary care hospital in Pakistan where both state of art management for covid infection and the primary malignancy was available. Majority of our patients were on active treatment and these results help prognosticate; patients who require intensive care carry a very grim prognosis. Data such as ours are especially important in formulating guidelines that are country/region specific regarding management of covid infections in a specific subset of patients. This is of importance in guiding management decisions in situations where resources are limited, and medical care is not covered by private insurance.
The expertise in management of covid infection has evolved over the last year. Early use of dexamethasone, remdesivir and anticoagulation has resulted in improved outcomes. Nonetheless, determine the incidence and severity of infections in cancer patients who have been adequately vaccinated.
In summary, this study of patients with hematological malignancy and COVID-19 accentuates several significant considerations for clinical care and emphasizes the urgent need for more data.
Longer-term follow-up and larger sample sizes are needed to understand the effect of SARS-CoV-2 on outcomes in patients with hematological malignancy.
The data is available to the corresponding authors and can be provided on the reasonable request.